Methods for the treatment of psychic disturbances

ABSTRACT

Cyproterone and its 17-esters are administered to persons with a psychic disturbance of the affective or behavioral type to evoke an anxiolytic response.

United States Patent Itil et al.

METHODS FOR THE TREATMENT OF PSYCHIC DISTURBANCES Inventors: Turan M.Itil, Nyack, N.Y.; Werner Martin Herrmann, Berlin, Germany Assignee:Schering Aktiengesellschaft, Berlin,

Germany Filed: Sept. 6, 1974 Appl. No.: 503,733

Foreign Application Priority Data Sept. 6, 1973 Germany 2345377 US. Cl.424/242 Int. Cl. A61K 27/00 [451 July 15,1975

2/1966 Wiechert et al. 260/239.55 R

Primary Examiner-Stanley J. Friedman Attorney, Agemy or FirmMillen,Raptes & White [5 7 ABSTRACT Cyproterone and its l7-esters areadministered to persons with a psychic disturbance of the affective orbehavioral type to evoke an anxiolytic response.

5 Claims, No Drawings METHODS FOR THE TREATMENT OF PSYCHIC DISTURBANCESBACKGROUND OF THE INVENTION This invention relates to medicinal agentscomprising cyproterone or a l7-ester thereof and to their use.

Cyproterone (6-chloro- 1 a,2oz-methylene-4,6-pregnadien-l7a-ol-3,20-dione) and the 17-esters thereof are known, forexample, from US. Pat. No. 3,234,093.

Several steroids are known to exert a depressant effect on the centralnervous system and possess hypnotic and/or anesthetic effects. Thesesteroids are not useful as psychotropic agents due to their known sideeffects and depression of the central nervous system.

Minor tranquilizers of the benzodiazepines type have become popular asmedicinal agents having an anxiolytic and sedative effect. However,these active agents have the disadvantage that their use can cause apsychic dependency (WHO Bull. 43 Suppl., 1970, 49). Furthermore, themuscle-relaxant properties of these substances, for example, can lead toundesired side effects (AMA Drug Evaluations, American Medical Assoc.Chicago, lst ed. 1971, pp. N 47 ff.). Also, the conventional anxiolytic(minor tranquilizer) and anti depressant (thymoleptic) substances havesedating properties which are undesirable during waking hours, e.g.,during work or activity which requires a person to be alert.

It has now been found that cyproterone and the esters thereof have abroader spectrum of effectiveness, compared to conventional minortranquilizers, with the additional advantage that they do not exhibitthe above-described adverse side effects, but instead have additionallyan antidepressant effect. This result has been obtained for the firsttime with a substance having a steroid structure.

SUMMARY OF THE INVENTION According to this invention, cyproterone or a17- ester thereof is administered systemically to a patient with apsychic disturbance of the affective or behavioral type in an amounteffective to evoke an anxiolytic response.

DETAILED DISCUSSION The preferred 17-esters of cyproterone are esters ofhydrocarbon carboxylic acids of l-8 carbon atoms, preferably 2-8 carbonatoms, e.g., a monobasic alkanoic acid, e.g., formic, acetic, propionicbutyric, isobutyric, oz-ethylbutyric, valeric, isovaleric,a-ethylvaleric, trimethylacetic, 2-methylbutyric, 3-ethylbutyric,hexanoic, diethylacetic, triethylacetic, enanthic, octanoic, a cyclicacid, preferably a cycloaliphatic acid, e.g., cyclopropylideneacetic,cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic,B-cyclopentylpropionic, cyclohexylcarboxylic, cyclohexylacetic, acarbocyclic aryl or an alkaryl acid, e.g., benzoic, 2-, 3- or 4-methylbenzoic acid.

A preferred class of acyl groups are those of straight or branched chainmonobasic alkanoic acids, preferably of 28 carbon atoms, e.g., acetyl,propionyl, butyryl, isobutyryl, of which acetyl is most preferred.

Since the exact chemical nature of the acyl radical of the 17-estergroup is not critical, as long as it is not physiologically toxic and itcan be formed on the cyproterone l7-hydroxy group, contemplatedequivalents of the preferred esters described above, insofar as they canbe formed, are those formed with other aliphatic and aromaticunsubstituted and substituted and monobasic, dibasic and polybasiccarboxylic acid, saturated or unsaturated aliphatic, araliphatic andaromatic carboxylic acids containing up to 18 and preferably up to 8carbon atoms, e.g.,undecylic, palmitic, B-cyclohexylpropionic acid,2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dimethylbenzoic, ethylbenzoic,2,4,6-trimethylbenzoic, cinnamic, naphthoic, 3-methyl-a-naphthoic,B-phenyL propionic, diphenylacetic, biphenylacetic or a-naphthylaceticacid, or a dibasic alkanoic acid, e.g., oxalic, maleic, fumaric,succinic, malonic, glutaric, a-methylglutaric, B-methylglutaric,B,B-dimethylglutaric, adipic, pimelic and suberic acid, a dibasic arylacid, especially those capable of forming a cyclic anhydride, e.g.,phthalic acid, or a carbamic acid, e.g., carbamic acid, phenylcarbarnic,n-butylcarbamic, dimethylcarbamic, diethylcarbamic and allophanic acid;or of a heterocyclic acid, e.g., B-furylcarboxylic pyrrole carboxylic,B-pyrrolidylpropionic, N-methylpyrrolidyL 2-carboxylic, -0z-picolinic,nicotinic, indole-2- carboxylic, 6-hydroxyindolyl-3-acetic and N-methylmorphol'yl-2-carboxylic and pyrrolyl-2- carboxylic acidfor asulfonic acid of 118, preferably 1-12, carbon atoms, includingalkanesulfonic, e.g., methaneand ethanesulfonic, and aryl sulfonic,e.g., benzeneand p-toluenesulfonic acid.

Such contemplated equivalents can also be esters with an acid containingone, two or more simple substituents in the molecule, e.g., hydroxy,halo, alkoxy, acyloxy, sulfonyloxy, amido, sulfato, nitro, mercapto andcyano, in the molecule, e.g., glycolic, lactic, citric, tartaric,d-maleic, d-glyceric, mannoic, gluconic and salicylic acid; of an aminoacid, e.g., glycine, aminopropionic, diglycollamic, triglycollamic,methylglycine, dimethylglycine, diethylglycine, para-aminosalicylic,paraaminobenzoic, ethylmercaptoacetic, benzylmercaptoacetic,chloroacetic, fiuoroacetic, trichloroacetic, trifluoroacetic,thioglycolic, m-nitrobenzoic, 2,3,4- trimethoxybenzoic, phenoxyaceticand a-naphthoxyacetic acid.

Cyproterone acetate was tested in a placebocontrolled double blankexperiment by quantitative pharmaco-electroencephalography (CEEG) and bythe method of evoked potentials on humans (T.M. Itil et a]. QuantitativePharmaco-Electroencephalography [The use of computerized cerebralbiopotentials in psychotropic drug research] in Psychotropic Drug andthe Human EEG, Modern Problems of Pharmacopyschiatry Series, Basel, NewYork: S. Karger, 1974).

Moreover, the effects and side effects were determined by various ratingscales, e.g., for neurological and psychosomatic symptom spectra, byself-rating scales for sedation, fear and depression, as well as byinterviews with physicians. In clinical tests, the effectiveness ofcyproterone acetate was proven in premenstrual anxiety and tensionconditions. The effectiveness was described by physicians judgments andplaced into objective form in ratings. In the practical application ofcyproterone and the esters thereof, the effect according to thisinvention occurs soon after administration, which is surprising since itis generally known from endocrine-active steroids that such effects areobserved only after a longer treatment period. In the case ofcyproterone acetate, in its previous applications for its known effects,such effects were known to occur only after weeks of treatment. Whereas,the desired psychotropic effects of cyproterone or its l7-esters, occurwithin hours after administration.

A particular advantage of the medicinal agents based on cyproterone or al7-ester thereof in the present field of application of this inventionis that, even during long-term usage, dependency does not arise and notolerance requiring higher dosages is observed, as occurs, for example,in the case of the benzodiazepines. Additionally, even with high doses,there is no danger of impairing the functional power and reactioncapacity, or of lowering the level of consciousness to produce a type ofdrowsiness, for example during driving or working.

Furthermore, it is also advantateous that cyproterone and the l7-estersthereof, even in a massive single oral dose of the order of 2 g., do notordinarily produce adverse neurological, vegetative or other sideeffects, or any disturbance of consciousness. Therefore, even anoverdose does not lead to serious muscle relaxation and impairment ofconsciousness.

During the further development of psychopharmaceuticals based onbenzodiazepines, a dissociation between the sedative and anxiolyticproperties was sought.

With cyproterone and its l7-esters, a class of compounds has been foundfor the first time which has the typical activity profile of ananxiolytic agent, but does not have any significant sedating properties.

Cyproterone and its l7-esters exhibits a neuropsychotropic effect of thetype of the minor tranquilizers and especially anxiolytic,antidepressant (thymoleptic) and sedative activity.

Accordingly, cyproterone and the l7-esters thereof possess the advantagethat they overcome the deficiency of lack of dissociation betweensedative and anxiolytic properties present in the knownpsychopharmaceuticals based on benzodiazepines.

In its method of use aspect, this invention relates to the treatment ofpsychic disturbances in the affective and behavioral ranges, especiallyanxiety and tension conditions, with and without depression, unrest anddisturbances resulting from stress situations or excess stimulation, aswell as pathological aggressiveness, employing cyproterone or a l7-esterthereof.

In medical practice, the drugs based on cyproterone and l7-estersthereof according to the present invention can be administeredsubcutaneously, intramuscularly or orally with effectiveness byinjection or oral administration being about equal. The daily dosage is0.05 500 mg., preferably 0.1- 50 mg. This dosage can be administered ina single oral dose. It is advantageous to remain below the thresholdvalue of endocrine effectiveness, especially under the threshold valuefor an antiandrogen effect in males and females of 50 to 100 mg per day.

The formulation of the medicinal agents of this invention isaccomplished in a conventional manner, by processing cyproterone and theesters thereof, especially the esters with l-8 carbon atoms, togetherwith the vehicles, diluents and flavor-ameliorating substance, customaryin galenic pharmacy, and then converting the compositions into thedesired forms of application, such as, for example, tablets, dragees,capsules and solutions suitable for oral or parenteral administration.

Especially suitable for injections are oily solutions, such as solutionsin sesame, castor and cottonseed oil.

If desired, diluents or solubilizers, such as, for example, benzylbenzoate or benzyl alcohol, can be added to increase solubility. Toobtain a protracted effect, cyproterone and the esters thereof can alsobe utilized in microencapsulated form. For oral application, especiallysuitable are capsules, tablets, dragees, pills, suspensions andsolutions. The amount of active agent in the thusformulated medicinalagents is 0.05 500 mg., preferably 0.1 50 mg., per unit dose.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the specification and claims in any way whatsoever.

EXAMPLE I 50.0 mg. of 6-chloro-17-acetoxy-l0:,20z-methylene-4,6-pregnadiene-3,20-dione (cyproterone acetate) is mixed homogeneouslywith 110.5 mg. of lactose, 59.5 mg. of corn starch, 2.0 mg. ofAerosil,2.5 mg. of polyvinylpyrrolidone 25, and 0.5 mg. of magnesium stearateand compressed, without previous granulation, into round, biplanartablets with a breaking notch and a final weight of 225 mg.

EXAMPLE 2 To produce an injection solution, 100.0 mg. of cyproteroneacetate is dissolved in 618.6 mg. of benzyl benzoate (USP XVII) and353.4 mg. of castor oil (DAB [German Pharmacopoeia] 7, USP XVII); thesolution is filtered under sterile conditions and filled asepticallyinto 3-ml. ampoules.

EXAMPLE 3 Respectively 0.1 mg. of cyproterone acetate (micronized,particle size 2-8 IL) is mixed homogeneously with mg. of lactose (DAB 7,USP XVII) and filled into hard-gelatin capsules (5 X 15 mm.).

EXAMPLE 4 Analogously to Example 1, 10 mg. of cyproterone is compressed,with 110.5 mg. of lactose, 59.5 mg. of corn starch, 2.0 mg. ofAerosil,2.5 mg. of polyvinylpyrrolidone 25, and 0.5 mg. of magnesium stearate,into tablets having a final weight of mg.

EXAMPLE 5 This study was set up in a group of five very young malepatients in the age range of 18-26, who are suffering from symptoms ofanxiety and they were included in this study. All patients receivedanxiolytics or similar treatment but not systematically and no longerperiod of time before cyproterone acetate treatment. All patients arecharacterized by nervousness, restlessness, anxiety, headache, andtachycardia. Before cyproterone acetate medication, all drugs werediscontinued and during the study no additional medication was allowed.The treatment period was 2 weeks and the daily dosages ranged from 1-6mg (mean 3.7-4.7 mg) (total dosage 55-57 mg).

In two patients complete remission with the improvement of symptoms ofanxiety, somatic symptoms, headache was observed (Patient 2 and 3). Inone patient a moderate degree of improvement was observed in dosages 3-4mg daily (Patient 4). When the dosage was increased patient gotrestless. In two other patients (Patient l and 5), only slightimprovement was observed in symptoms such as restlessness, parasthesia,difficulty in swallowing, tachycardia, and insomnia.

EXAMPLE 6 Cyproterone acetate was administered to 10 female patients inthe age range of 25-55. All patients had clinical symptoms of anxiety,depression or psycho-physiological complaints which appear either in thepremenstrual period or if already present, showed marked exacerbationafter midcycle.

The patients were medicated for two cycles, one with placebo and onewith cyproterone acetate. Treatment was started immediately followingthe appearance of clinical symptoms and continued until a few daysbefore the estimated date of the beginning of the next cycle.Cyproteronc acetate and placebo were given at 100 mg once a day in themorning. All patients showed a significant remission of anxiety-tensionand depression during the premenstrual period.

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

l. A method for the treatment in a affected person of psychicdisturbances of the affective or behavioral type which comprisesadministering systemically to the af fected person an amount ofcyproterone or a 17-ester thereof with a hydrocarboncarboxylic acid ofl-8 carbon atoms effective to evoke an anxiolytic response.

2. A method according to claim 1 wherein cyproterone is administered.

3. A method according to claim 2 wherein the cyproterone is administeredorally.

4. A method according to claim 1 wherein cyproterone acetate isadministered.

5. A method according to claim 4 wherein the cyproterone acetate isadministered orally.

1. A METHOD FOR THE TREATMENT IN A AFFECTED PERSON OF PSYCHICDISTURBANCES OF THE AFFECTIVE OR BEHAVIORAL TYPE WHICH COMPRISESADMINISTERING SYSTEMICALLY TO THE AFFECTED PERSON AN AMOUNT OFCYPROTERONE OR A 17-ESTER THEREOF WITH A HYDROCARBONCARBOXYLIC ACID OF1-8 CARBON ATOMS EFFECTIVE TO EVOKE AN ANXIOLYTIC RESPONSE.
 2. A methodaccording to claim 1 wherein cyproterone is administered.
 3. A methodaccording to claim 2 wherein the cyproterone is administered orally. 4.A method according to claim 1 wherein cyproterone acetate isadministered.
 5. A method according to claim 4 wherein the cyproteroneacetate is administered orally.